Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19

Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females. ### Competing Interest Statement MTM reports grants on biomarker diagnostics from the Defense Advanced Research Projects Agency (DARPA), National Institutes of Health (NIH), Sanofi, and the Department of Veterans Affairs. TWB reports grants from DARPA and is a consultant for Predigen; MTM, TWB, ELT, GSG, and CWW report patents pending on Molecular Methods to Diagnose and Treat Respiratory Infections. ELT reports grants on biomarker diagnostics from DARPA, the NIH/Antibacterial Resistance Leadership Group (ARLG) ; an ownership stake in Predigen; GSG reports an ownership stake in Predigen; CWW reports grants on biomarker diagnostics from DARPA, NIH/ARLG, Predigen, and Sanofi; and has received consultancy fees from bioMerieux, Roche, Biofire, Giner, and Biomeme.